MXPA96004657A - Acidos piperidina- and pirrolidina-carboxilicos antiadhesi - Google Patents

Abstract

The invention relates to conjugates consisting of piperidine or pyrrolidine derivatives one or more times carboxylated and in pyranose, furanose or polyalcohols linked through a chain or a cycle. The carboxyl groups of the piperidine derivatives can settle directly in the ring or be linked to the ring through a short chain. The invention also relates to the preparation of these compounds, as well as to their use for the preparation of medicaments and diagnostic agents.

Description

Anti-adhesive piperidine- and pyrrolidine-carboxylic acids The invention relates to conjugates consisting of piperidine or pyrrolidine derivatives one or more times carboxylated and in pyranose, furanose or polyalcohols linked through a chain or a cycle. The carboxyl groups of the piperidine derivatives can settle directly in the ring or be linked to the ring through a short chain. The invention also relates to the preparation of these compounds, as well as to their use for the production of medicaments and diagnostic agents.

The circulation of blood cells, such as for example leukocytes, neutrophils, granulocytes and monocytes, in a molecular plane, is a very complex and multistep process, which is only known in partial steps (reviewed article: TA Springer, Cell 76, 301-314, 1994). Recent research results showed that the lymphocyte recirculation, which is decisive in immune surveillance, as well as the location of neutrophils and monocytes in inflammatory foci, obeys very similar molecular mechanisms. Thus, in the case of acute and chronic inflammatory processes, the adhesion of leukocytes to endothelial cells and migration to the inflammatory focus and secondary lymphatic organs occurs. Numerous specific signal molecules are involved in this process, such as for example interleukins, leukotrienes and tumor necrosis factor (TNF), their G protein-coupled receptors and, in particular, adhesion molecules to tissue-specific cells. that guarantee a precisely controlled recognition of immune and endothelial cells. The most important adhesion molecules involved in this case, which in the following are called receptors, belong to the selectives (E, P and L selectins), integrins and members of the immunoglobulin superfamily.

The three receptors of selectin determine the initial phase of leukocyte adhesion, Selectin E is expressed in endothelial cells a few hours after stimulation, for example by interleukin-1 (IL-13) or tumor necrosis factor (F Ta).;), whereas P-selectin is stored in blood platelets and endothelial cells and occurs, inter alia, on the surfaces of cells after stimulation by thrombin, peroxide radicals or substance P. Selectin L expresses permanently on leukocytes, but in the course of inflammation is rapidly dissociated again by leukocytes.The inflammatory processes in the initial phase by adhesion of leukocytes to endothelial cells, induced by selectin receptors, is- a natural immune response and necessary to various inflammatory stimuli and vascular tissue lesions, however, the course of a series of acute and chronic diseases it is affected unfavorably, in the sense of an autoimmune reaction, by the excessive adhesion of leukocytes and its infiltration in the affected tissue, as well as by the injury of healthy tissue. These include, for example, rheumatism, reperfusion injury, such as ischemia / myocardial infarction (MI), acute lung inflammation after surgery, traumatic shock and stroke, psoriasis, dermatitis, ARDS (dyspnea syndrome in adults), as well as the restenosis that manifests itself after surgical interventions (for example, angioplasty and by-pass arterial bypass operations). The natural ligand with the structure of SLeX has already been used successfully in animal tests in the case of pulmonary lesions dependent on P-selectin (MS Mulligan et al., Nature 1993, 364, 149) and in the case of reperfusion injuries. Myocardial surgery (M. Buerke et al., J. Clin. Invest. 1994, 93, 1140). In early clinical trials in the case of acute lung inflammation, the compound should be used in a dose of 1-2 grams per day and patient (Information from the Cytel Corp. / La Jolla (CA) company at the 2nd Meeting of Glicotechnology / CHI in La Jolla / USA, May 16-18, 1994). This high dose of active principle is in accordance with the known weak affinity of natural SLeX / A ligands for the selectin receptors. A) Yes, SLeX inhibits in all known in vitro assay systems the adhesion of cells to selectin receptors only in the case of a relatively high concentration in the range of CIS0 approx. 1 mM (Jacob et al., Biochemistry 1995, 34, 1210). In some publications and patent applications, meanwhile, efforts were made to access, by structural variation of the ligand, antagonists that are firmly attached. The objective of these works is the provision of more effective antagonists that would also be potentially employable in vivo in the case of lower doses. The variation of the fucose and neuraminic acid components considered as decisive until now for the structure-effect relationship - (BK Brandley et al., Glycobio-logy 1993, 3, 633 and M. Yoshída et al., Glycoconjugate J. 1993, 10, 3) did not provide, however, any significantly improved inhibition value. Only in the case of the variation of the glucosamine component (replacement of GlcNAc by glucose and azidO 'groups as well as amino in position 2 of GlcNAc), a significantly increased affinity could be achieved at the E-selectin receptor. On the contrary, in the P-selectin receptor, no improved binding was achieved. The IC50 data of these oligosaccharide derivatives have to be found, for the inhibition of the adhesion of HL-60 and U-937 cells, in 0.12 mM (compared to 1.2-2.0 mM for SLeX) in the case of select.ina E. On the contrary, it is disadvantageous that the fixation to selectins L and P with >; 5 mM is strongly impaired (Dasgupta et al., Poster presentation of the company Glycoméd Inc. on the occasion of the Session in La Jolla on 5/94). In general, hitherto all successes to improve the binding affinity of SLeX and SLeA derivatives have been limited to the selectin E receptor, since with the P-selectin receptor only weak effects of inhibition were found at inhibitor concentrations of about 1 mM (RM Nelson et al., J. Clin Invest 1993, 91, 1157). The known state of the art concerning the binding affinity of modified SLeX / A structures in selectins is reviewed in Pharmacochem. Libr. 1993, 20 (Trends in Drugs Research), pages 33-40. The object of the present invention is the production of new selectin ligands which have a clearly stronger binding to the receptors compared to natural ligands and which, moreover, can be synthesized more easily than these. The established problem is solved by a compound of the formula I wherein Z means a pyranoside, a pyranosyl radical linked through the C6 position, an alkyl-pyranoside linked through the C6 position, a furanoside, a furanosyl radical linked through the C5 position, an alkyl furanoside linked through position C5 or a polyalcohol which is bonded to A through an arbitrary position, A means oxygen, -CH2- or sulfur, R1 and R2, independently of one another, mean hydrogen, - (CH2) mX1 or CH20 (CH2) mX2, meaning m an integer from 1 to 20, or together they mean a carbocyclic or heterocycle of five or six members with at least one of the substituents R4, R5 or R6, E means nitrogen, carbon or - CH-, R3 signifies - (CH2) pCOOH, (-COOH) 2, - (CH2) pCH (C00H) 2, - (CH-) pCNH2 (COOH) 2, - (CH2) pC (CH2-C6H5) (COOH) ) 2, -C0NHC (C00H) 2, meaning p an integer from 0 to 10, or CH- -OH 0 = \ OH qyr, independently of one another, mean an integer from 0 to 3, n means an integer from 1 to 3, with the proviso that the sum of q, ryn amounts to 4 or 5, R \ Rs and R6, independently one of another, they mean H, OH, -0 (CH2) "X3 or CH20 (CH2)" X4, meaning an integer of the 18, Y1 and Y2, independently of one another, mean oxygen, -NH- or sulfur and X1, X2, X3 and X4, independently of one another, mean hydrogen, -NH2, -COOH, -OH, -CH2OH, CH2NK2, alkyl, C3-C10 aryl. The compound of the formula I is preferred, characterized in that R1 and R2 together form a cyclohexane ring or together form a cyclopentane ring. Preferably, A, Y1 and Y2 in formula I mean oxygen. Particularly preferred compounds according to the present invention are furthermore distinguished because Z in formula I means a pyranoside, preferably an L-fu-coside, a D-mannoside, L-rhamnoside, L-galactoside or an L-ma-noside . Also particularly suitable are compounds of the formula I, which are characterized in that Z is a furanoside, preferably a riboside. Other preferred embodiments of the present invention are distinguished in that Z in formula I is a D-mannosyl radical linked through the C6 position or a methyl-D-mannoside likewise linked. Z in formula I preferably also means an L-threit-1-yl radical. Preferred embodiments of the heterocycle in formula I formed by N (nitrogen), (CH2), (CH2) ry (R3-E) n are distinguished because n means 1 and qyr mean 2, nyr mean 1 and q means 3, n means 1, q means 0 and r means 3. The substituent R3 in formula I preferably means - (CH2) pC00H, where p 0, or - (CH2) pCH (COOH) 2, where p 1, where in both cases the variable E means preferably -CH-. Preferably, R3 also means (-COOH) 2, represented E carbon. Next, examples for compounds with the aforementioned preferred properties are presented. A compound of the formula I, which is distinguished by the fact that Z means a pyranoside, for example an L-fucoside and A, Y1 and Y2 mean oxygen, 'R1 and R2 together form a cyclohexane ring, R3 means (CH2) pCOOH , E means -CH-, n means 1, qyr means 2 and p means 0, for example 2. A compound of formula I, which is distinguished because Z means a pyranoside, for example an L-fucoside and A, Y1 and Y2 mean oxygen, R1 and R2 together form a cyclohexane ring, R3 means (CH2) pCH (C00H) 2, E means -CH-, nyr mean 1 , q means 3 and p means 1, for example 3. A compound of formula I, which is distinguished because Z means a pyranoside, for example an L-fucoside and A, Y1 and Y2 mean oxygen, where R1 and R2 together form a cyclohexane ring, R3 means (COOH) 2, E means carbon, n means 1 and q and r means 2, for example 4. A compound of the formula I, which is distinguished because Z means a pyranoside, for example an L-rhamnoside and A, Y1 and Y2 mean oxygen, R1 and R2 together form a cyclohexane ring, R3 means (CH2) pC00H, E means -CH-, p means 0 and n means 1 and qyr means 2. for example . A compound of the formula I, which is distinguished by the fact that Z means a pyranoside, for example, L-fucoside and A, Y1 and Y2 mean oxygen, where R1 and R2 together form a cyclopentane ring, and R3 means (CH2) pCOOH , E means -CH-, p means 0 and n means 1 and qyr means 2, for example 6. A compound of formula I, which is distinguished because Z means a pyranoside, for example an L-fucoside and A, Y1 and Y2 mean oxygen, wherein R1 and R2 together form a cyclohexane ring, and R3 signifies (CH2) pCH (COOH) 2, p means 1, E means -CH-, and n means 1, q means 0 and r means 3, for example Other examples are compounds of formula I, which are distinguished because R1 and R2 together form a cyclohexane ring, and Ar YJ and Y2 mean oxygen, where n means 1 and qyr mean 2, R3 means (CH2) pCOOH, E means - CH-, p means 0 and 7. Z represents a radical L-treit, -l-yl, for example HO Z represents an alkylpyranoside linked through the C6, 8 position. For example, it represents a methyl-v-D-mannopyranoside, or 9. for example, a methyl- / ß-D-galactopyranoside or 10, Z represents a pyranosyl radical linked through the Cs position, for example a galactosyl radical, for example The problem established at the beginning is also solved by a process for the preparation of a compound of the formula I, characterized in that it is first prepared, under glycosylation at 0 or S, alkylation or CC bond of a functional group of an acceptor of formula II, having at least two contiguous L1 and L2 functional groups, as well as having the substituents R1 and R2, by an equivalent of a donor of the formula III III, provided with an activating group L3 and optionally protective groups, intermediate IV R2 after which, under reaction with the reagent of formula V, where L * and L5 have the meaning of labile groups, the activated compound is accessed VI which, by reaction with a cyclic amine carboxylated once or several times or a suitable precursor thereof and optionally after cyclization or carboxylation, as well as after separation of protecting groups, is transformed into the compound of formula I, the variables R1, R2, Yx, Y2, A and Z having the meanings mentioned. The compounds of the general formula I according to the invention can be prepared starting from commercially available components with at least 2 contiguous functional groups (acceptor II), such as for example (IR, 2R) -trans-1, 2- cyclohexanediol or tri-O-acetyl-D-glucal. In the case of these compounds, for example (in the first case) by glycosylation with a carbohydrate donor (for example trichloroacetimidate, ethylglycoside, etc.) or alkylation with an activated polyalcohol (for example 1, 2, 3 tosylate) -tri-O-benzyl-L-threitol) the first of the two adjacent functional groups (for example a hydroxyl group) is reacted (intermediate IV). The functional group still remaining (L1, for example optionally a hydroxyl group) can then be reacted, for example with chloroformic acid nitrophenyl ester (reagent of the formula V with the leaving groups Cl and 0-C6H4-N02, to give the carbamate of nitrophenyl (compound VI), which, still in the same reaction vessel, reacts with a cyclic amine (for example ethyl ester of piperidine-4-carboxylic acid) or a suitable precursor [for example 3- (hydroxymethyl) -piperidine] to give compounds of the formula I or their precursors (see Example 4b) The compounds of the formula I according to the invention can have, in spite of their molar mass, substantially lower than the sialyl-Lewis X, a greater affinity than this for the natural receptors, for example by E and P selectin. This can be determined with the aid of the cell adhesion assay described below. essays To investigate the effect of compounds according to the present invention on the adhesion of cells to recombinant and soluble selectin fusion proteins. In order to test the activity of the compounds according to the invention with respect to the interaction between E and P selectins (old nomenclature ELAM-1 or GMP-140) with their ligands, an assay is used which is specific in each case. case only for one of these interactions. Ligands are offered in their natural form in the form of surface structures on promyelocytic HL60 cells. Since ligands of HL60 cells and adhesion molecules have the most diverse specificity, the desired specificity of the assay can only be achieved through the participant in the fixation. As binding partners, soluble fusion proteins prepared by genetic technology of the individual extra-plasma domains of E or P selectin and of the constant region of a human immunoglobulin of subclass IgGl are used.

Preparation of L-selectin-IgGl For the preparation of the soluble L-selectin-na-IgGl fusion protein the genetic construct "ELAM-Rg" published by Walz et al., 1990 was used. For the expression, the plasmid DNA was transfected into COS-7 cells (ATCC) by DEAE-dextran (Molecular Biology methods: see Ausubel, FM, Brent, R., Kingston, RE, Moore, DD, Seidman, JG, Struhl, K. and Smith, JA 1990. Current Protocols in Molecular Biology, John Wiley, New York). Seven days after the transfection, se. obtained the culture supernatant, it was released from cells and cell fragments by centrifugation and was taken to 25 mM Hepes, pH-7.0, 0.3 mM PMSF, 0.02% sodium azide and conserved to + 4 ° C. (alz, G., Aruffo, A., Kolanus,., Bevilacqua, M. and Seed, B. 1990, Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells, Science 250, 1132-1135) .

Preparation of P-IgGl selectin For the preparation of the selectin fusion protein Soluble P-IgGl the genetic construct "CD62Rg" published by Aruffo et al., 1991 is used. The subsequent procedure corresponds to the preparation of selectin L-IgGl represented in section Al. Aruffo, A., Kolanus, W., alz, G., Fredman, P. and Seed, B. 1991, CD62 / P-Selectin recognition of myeloid and tumor cell sulfatides. Cell 67, 35-44.

Preparation of CD4-IgGl For the preparation of the soluble CD4-IgGl fusion protein, the genetic construct "hinge CD4: IgG1" published by Zettlemeissl et al., 1990 is used. The subsequent procedure corresponds to the preparation of L-selectin. IgGl discussed in section Al. (Zettelmeissl, G., Gregersen, J.-P., Duport, JM, Mehdi, S., Reiner, G. and Seed, B. 1990. Expression and characterization of human CD4; Immunoglobulin Fusion Proteins, DNA and Cell Biology 9, 347-353).

Carrying out the adhesion assay of HL60 cells to soluble adhesion molecules and recombinants 1. 96-well titration assay microplates (Nunc Maxisorb) are incubated at room temperature for 2 hours with 100 μl of an anti-human IgG antibody. of goat (Sigma) diluted in 50 mM Tris pH 9.5 (1 + 100). After removing the antibody solution, it is washed once with PBS. 2. 150 μl of the blocking buffer is left for 1 h at room temperature in the wells. The composition of the blocking buffer is: 0.1% gelatin, 1% BSA, 5% calf serum, 0.2 M PMSF, 0.02% sodium azide. After removing the blocking buffer, it is washed once with PBS. 3. In the wells, 100 μl of supernatant from the culture of COS cells correspondingly transfected and expressed is pipetted in each case. Incubation is carried out for 2 h at room temperature. After removing the supernatant from the cell culture, it is washed once with PBS. 4. To the wells, 20 μl of binding buffer is added. The binding buffer has the composition: 50 mM Hepes, pH 7.5; 100 mM NaCl; 1 mg / ml BSA; 2 mM MgCl 2; 1 mM CaCl 2; 3 mM MnCl2; 0.02% sodium azide; 0.2 mM PMSF. To this, 5 μl of the test substance are pipetted, mixed by tilting the plate and = and incubated for 10 min at room temperature. . 50 ml of a culture of HL60 cells with 200,000 cells / ml are centrifuged for 4 min at 350 g. The pellet is resuspended in 10 ml of RPMI 1640 and the cells are centrifuged again. For the labeling of the cells, 50 μg of BCECF-AM (molecular probes) are dissolved in 5 μl anhydrous DMSO; then 1.5 ml of RPMI 1640 is added to the BCECF-AM / DMSO solution. With this solution, the cells are resuspended and incubated for 30 min at 37 ° C. After centrifugation for two minutes at 350 g, the labeled cell pellet is resuspended in 11 ml of binding buffer, and the cells resuspended in 100 μl of aliquots are distributed in the wells of the titration microplates. The plate is allowed to stand for 10 min at room temperature, in order to allow the cells to settle to the bottom of the test plate. In this case, the cells have the possibility of adhering to the coated plastic. 6. To stop the assay-, the titration microplate is immersed at an angle of 45 ° completely in the stop buffer (Tris 25 mM, pH 7.5; 125 mM NaCl; 0.1% BSA; 2 mM MgCl 2; 1 mM CaCl 2; 3 mM MnCl2; 0.02% sodium azide). By inversion, the stop buffer is removed from the wells and the process is repeated for two times. 7. The measurement of cells labeled with BCECF-AM and strongly adhered to the wells is carried out in a cyto-fluorometer (Millipore) at a sensitivity setting of 4, an excitation wavelength of 485/22 nm and a length of emission wave of 530/25 nm.

Results: IC50 values for E [mM] selectin, in parentheses for P [M] selectin: N-carbonyl -4-carboxypiperidyl- (1? 2) - [(α-L-fucopyranosyl) - (l- * l)] - (IR, 2R) -trans-l, 2-cyclohexanediol (3a): greater than 2 (greater than 2) [N-carbonyl- (1, l-dicarboxyl-ethyl) - (2? 3) -piperidyl] - (1? 2) - [(a-L-fucopyranosyl) - (I?) ] - (IR, 2R) -trans-l, 2-cyclohexanediol (4b): greater than 2 (greater than 2) N-carbonyl-4-carboxypiperidyl- (1? 2) - [(aL-fucopyranosyl) - ( (I)) - (IR, 2R) -trans-l, 2-cyclopentadiol (le): 3.7 (2.85) N-carbonyl-4,4-dicarboxypiperidyl- (1? 2) - [(O) -L-fucopyranosyl) - (1)] - (IR, 2R) -trans-1, 2-cyclohexanediol (3e): 1.6 (7.5) Adhesion of leukocytes-Examination of the in vivo activity of the compounds according to the invention (intravital microscopy in rats): In the case of inflammatory processes and other cytokine activating states, the destruction of tissues by means of leukocytes or immigrants that block the icrocircu -lation, plays a decisive role. The first phase, decisive for the subsequent process of the disease, is the activation of leukocytes within the bloodstream, particularly in the precapillary and postcapillary area. In this case, once the leukocytes have left the axial flow of blood, a first adhesion of the leukocytes to the inner wall of the vessels, that is to say in the endothelium of the vessels, occurs. All the effects of the leukocytes that follow, ie the active passage through the vessel wall and the subsequent tissue-oriented migration, are consecutive reactions (Harán, JM, Leukocyte-endothelial interaction, Blood 65, 513 -525, 1985). This interaction of leukocytes and endothelial cells induced by receptors is considered an initial sign of the inflammatory process. Together with the adhesion molecules already physiologically expressed, under the influence of inflammation mediators (leukotrienes, PAF) and cytokines (TNF-alpha, interleukins) a massive and stepwise expression of adhesion molecules on the cells takes place. . Currently, they are divided into three groups: 1. superfamily of immunoglobulin genes, 2. integrins and 3. selectins. While the adhesion runs between molecules of the Ig gene superfamily and the protein-protein linkages, the selectin-carbohydrate bonds stand out in the cooperation between selectins (Springer, TA, Adhesion receptors of the immune system.) Nature 346, 425-434, 1990; Huges, G., Cell adhesion molecules - the key to universal panacea, Scrips Magazine 6, 30-33, 1993; Springer, TA, Traffic signs for lymphocyte recirculation and leukocyte emigration; The multistep paradigm. 76, 301-314, 1994).

Method: The induced adhesion of leukocytes is quantified with a research technique by intravital microscopy in the mesentery of the rat (Atherton A. and Born GVR, Quantita-tive investigations of the adhesiveness of circulating polymorphnuclear leukocytes to blood vessel walls J. Physiol 222, 447-474, 1972; Seiffge, D. Methoden zur Untersuchung der Rezeptor-see ittelten Interaktion zwischen Leukozyten und Endothelzellen in Entzündungsgeschehen, in: Ersatz- und Ergánzungsmethoden zu Tierversuchen in der Biomedizinischen Forschung, Schóffl, H. et al., (ed.) Springer, 1995 (in print phase) Under anesthesia with ether by inhalation a permanent narcosis is initiated by intramuscular injection of urethane (1.25 mg / kg body weight) After the dissection of the vessels ( femoral vein for the injection of substances and carotid artery for the measurement of blood pressure) catheters are attached to them, then the transparent tissue runs The material (mesentery) is left uncovered according to standard methods known in the literature and is spread "on the microscope table and coated with paraffin oil heated to 37 ° C (Menger, M.D. and Lehr, H., A. Scope and perspectives of intravital microscopy-bridge over from in vitro to in vivo, Immunology Today 14, 519-522, 1993). The test substance is applied i.v. in the animal (10 mg / kg). The experimental increase in the adhesion of blood cells is triggered by cytokine activation by systemic administration of lipopolysaccharide (LPS, 15 mg / kg), 15 minutes after the application of the test substance (Foster SJ, Me. Cormick LM, Ntolosi BA and Campbell D., Production of TNF-alpha by LPS - stimulated murine, rat and human blood and its pharmacology-cal modulation, Agens and Actions 38, C77-C79, 1993, 18.01.1995). The increased adhesion of leukocytes in the endothelium, caused thereby, is quantified directly by vital microscopy or with the aid of fluorescent dyes. All measurement processes are recorded by a video camera and stored in a video recorder. The number of rolling leukocytes (ie, all visibly rolling leukocytes which are slower than flowing erythrocytes) and the number of leukocytes attached to the endothelium are determined every 10 minutes over a time interval of 60 minutes. of permanence greater than 5 seconds). After the end of the test, the drugged animals are numbed painlessly and free of excitation by systemic injection of T61. For the evaluation, the results of in each case 8 treated animals are compared with 8 untreated animals (control group) (data of the results in percentages).

Results: 3a: Dosage: 10 mg / kg; application: i.v .; species: SPRD (m), - weight in g: 298 ± 17.72; number of vessels: 15; diameter of the vessels in μM 24 + 5; leukocytes at 103 / mm3: 7.7 ± 2.66; fibrinogen in mg / 100 ml: 135 ± 21.71; inhibition: 81%. Dosage: 5 mg / kg; application: i.v .; species: SPRD (m); weight in g: 306 ± 6.65; number of vessels: 16; diameter of the vessels in μM 27 + 4; leukocytes in 103 / mm3: 7.5 ± 1.93; fibrinogen in mg / 100 ml: 101 ± 5.75; inhibition: 69%. Dosage: 1 mg / kg; application: i.v .; species: SPRD (m); weight in g: 333 ± 21.6; number of vessels: 16; diameter of the vessels in μM 25 ± 4.1; leukocytes at 103 / mm3: 7.3 ± 1.4; fibrinogen in mg / 100 ml: 117 ± 15.8; inhibition: 64%.

Reperfusion model for the investigation of the influence of neutrophil adhesion in the course of ischemia / reperfusion in the open heart of rabbits. Hearts are perfused at constant pressure according to the Langendorff technique with nutrient solution as well as without leukocytes or active substance. Then ischemia is caused by ligation of the left coronary artery (30 min). After reperfusion (30 min), the accumulation of leukocytes is histologically evaluated. In the trans-course of the test, potentials and arrhythmias are measured in 256 electrodes (total duration of the test, approximately 90 min). In 6 of 7 perfused hearts, not treated with leukocytes, marked arrhythmias are manifested by virtue of leukocyte infiltration, whereas hearts treated with an active substance (RGDS peptides, chondroitin sulfate) develop a reduced accumulation of leukocytes and arrhythmias. The compound 3a investigated was very active in the range of approximately 1 μM (strong reduction of arrhythmias). The compounds according to the present invention, as well as their physiologically compatible salts, are suitable, by virtue of their valuable pharmacological properties, very well for their application as curative agents in mammals, in particular man. Therefore, the present invention also relates to a medicament containing at least one compound according to formula I, as well as to its use for the preparation of a medicament for the therapy or prophylaxis of diseases that are accompanied by an adhesion of cells in the tissue affected by the disease, excessive and induced by selectin receptors, for example rheumatism, diseases of the circulation of the heart, such as reperfusion injury, ischemia or heart infarction. The medicaments are suitable, in particular, for the treatment of acute and chronic inflammations which are characterized pathophysiologically by a disorder of the circulation of cells, for example of lymphocytes, monocytes and neutrophil granulocytes. These include autoimmune diseases, such as acute polyarthritis, rheumatoid arthritis and insulin-dependent diabetes (IDDM diabetes mellitus), acute and chronic rejection of transplants, pulmonary shock (ARDS, dyspnea syndrome in adults), inflammatory and allergic skin diseases. , such as for example psoriasis and contact eczema, diseases of the circulation of the heart, such as myocardial infarction, reperfusion injuries after thrombolysis, angioplasty or arterial bridging operations, septic shock and systemic shock. Another potential indication is the treatment of metastasizing tumors, since the tumor cells carry surface antigens possessing both sialyl-Lewis-X structures as well as sialyl-Lewis-A as recognition epitopes. In addition, these drugs, which are stable in the acid medium of the stomach, can be used for anti-adhesive therapy of Helicobacter pylori and related microorganisms, possibly also in combination with antibiotics. In addition, with the help of these drugs, a therapy of the cerebral form of malaria is conceivable. The medicaments according to the invention are administered, usually, intravenously, orally or parenterally, or in the form of implants, but rectal application is also possible in principle. Forms of suitable solid or liquid galenical preparations are for example granules, powders, tablets, dragees, (micro) capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in ampule form, as well as preparations with a release of the active ingredient, whose preparation usually finds application of support substances and additives and / or coadjuvants, such as disintegrating, binding, coating, expansion, glidants or lubricants, flavoring substances, sweetening agents or dissolving agents. Examples of frequently used support substances or adjuvants are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk albumin, gelatin, starch, vitamins, cellulose and their derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as, for example, sterile water, alcohols, glycerol and polyhydric alcohols. Preferably, the pharmaceutical preparations are prepared and administered in dosage units. Solid dosage units are tablets, capsules and suppositories. For the treatment of a patient, depending on the activity of the compound, type of application, type and severity of the disease, age and body weight of the patient, different daily doses are necessary. However, in certain circumstances, higher or lower daily doses may also be suitable. The administration of the daily dose can be effected both by single administration in the form of a single dosage unit as well as several small dosage units, as well as by multiple administration of divided doses at certain intervals. The daily dose to be administered may also be a function of the number of receptors expressed during the course of the disease. It is conceivable that in the initial phase of the disease only a few receptors are expressed on the surface of the cell and, therefore, the daily dose to be administered is lower than in the case of severely ill patients. The medicaments according to the invention are prepared by bringing a compound according to the present invention with support substances, as well as optional additives and / or adjuvants, into a suitable administration form. Furthermore, the use of compounds according to formula I for the preparation of an agent for the diagnosis of a disease accompanied by excessive cell adhesion, induced by selectin receptors, in the tissue affected by the disease is conceivable. Examples for the preparation of the compounds according to the invention: Example 1 a) Synthesis of [(2, 3, 4-tri-O-benzyl-aL-fucopyranosyl) - - (1?)] - (IR, 2R) -trans-1, 2-cyclohexanediol (la): A mixture based on (IR, 2R) -trans-l, 2-cyclohexanediol (2.43 g, 20.9 mmol), thioethyl-O-2, 3, 4-tri-0-benzyl-3-L- -fucopyranoside (8.0 g, 16.72 mmol) and tetrabutylammonium bromide (2.7 g, 8.36 mmol) in dichloromethane (200 ml) and DMF (40 ml) is stirred for 1 h with a molecular sieve of 4Á. Next, copper (II) bromide (5.6 g, 25.08 mmol) is added. After 24 h, it is filtered through diatomaceous earth, washed with saturated sodium hydrogencarbonate solution and then with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and chromatographed with hexane / ethyl acetate 3: 1. Yield: (6.8 g, 76%). "H NMR (300 MHz, CDC13): d = 1.13 (d, 3H, 6-Hfuc), 1.21 (m, 4H, 4-Hcyclohex, 5-Hcyclohex), 1.65, 2.01 (2m, 4H, 3-HciclohßX / 6 ~ Hcieiohß?) b) Synthesis of N-carbonyl-4-carboethoxypiperidyl- (1? 2) - - [(2,3,4-tri-O-benzyl-aL-fucopyranosyl) - (1?)] - (1R, 2R) - -trans-l, 2-cyclohexa-thiol (2a): To a solution based on (8.2 g, 15.39 mmol) in dichloromethane (164 ml) are added, at 0 ° C, triethylamine (2,3 ml, 16.9 mmol), DMAP (206 mg, 1.69 mmol) and chloroformic acid nitrophenyl ester (3.1 g, 15.39 mmol). The mixture is stirred overnight and combined with N-ethyldi-isopropylamine (4.6 ml, 26.9 mmol), as well as piperidine-4-carboxylic acid ethyl ester (4.15 ml, 26.9 milliliters). moles). Stir once more for 18 h. For the treatment, it is diluted with dichloromethane (500 ml) and washed with water (3 x 250 ml). The organic phase is concentrated in vacuo and chromatographed with hexane / ethyl acetate 3: 1 → 2: 1: 1. Yield: (9.3 g, 84%). LH-NMR (300 MHz, CDC13): d = 1.09 (d, 3H, 6-Hfuc), 1.25 (t, 3H, 0CH2CH3), 4.14 (q, 2H, 0CH2CH,). c) Synthesis of N-carbonyl-4-carboxypiperidyl- (1? 2) - [(aL- -fucopyranosyl) - (1?)] - (IR, 2R) -trans-1, 2-cyclohexanediol (3a) ): A mixture based on compound 2a (9.75 g, 13.6 mmol) and palladium on carbon (10%, 9 g) in eta-nol / dioxane / glacial acetic acid (50: 5: 2, 570 ml) ) is hydrogenated for 24 h at normal pressure in a hydrogen atmosphere. The paladic over charcoal is separated by filtration, the residue is concentrated and treated with 1 M sodium hydroxide solution (100 ml). After 2 h, neutralize with Ambelite IR-120 and purify through RP silica gel (C18 Bakerbond 60 Á) with water / methanol 9: 1: 9. Compound 3a is obtained (5.18 g , 91%). "H-NMR (300 MHz, D20): d = 1.05 (d, 3H, 6 -Hfuc), 1.56 (m, 2H), 1.78 (m, 3H), 2.00 (m, 1H), 2, 45 (m, 1H), 2, 80 (m, 2H), 4, 50 (m, 1H, 2-Hciolohßx), 4.87 (broad s, 1H, 1 -H £ uc).

Example 2 a) Synthesis of N-carbonyl-3- [(hydroxymethyl) -piperidyl] - - (1? 2) - [(2,3,4-tri-O-benzyl-aL-fucopyranosyl) - (l? l)] - - (IR, 2R) -trans-l, 2-cyclohexanediol (lb): Compound lb is prepared analogously to 3a. For this, it is reacted with chloroformic acid nitrophenyl ester and then 3- (hydroxymethyl) -piperidine (Aldrich) is added. The treatment is carried out as described in 3a. b) Synthesis of N-carbonyl-3- [(p-toluenesulfonyloxymethyl) -piperidyl] - (1? 2) - [(2,3,4-tri-O-benzyl-aL-fucopyranosyl) - (1) (I)) - (IR, 2R) -trans-l, 2-cyclohexanediol (2b): To an ice-cooled solution of compound lb (650 mg, 0.97 mmol) in pyridine (13 ml) is added chloride. p-toluenesulfonic acid (277 mg, 1.45 mmol). After 18 h, dichloromethane (100 ml) is added thereto and the organic phase is washed with saturated sodium chloride solution (2 x 50 ml). The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (hexane / ethyl acetate 2: 1) gives compound 2b (537 mg, 67%). ? -NRM (300 MHz, CDC13): d = 1.06 (d, 3H, 6-Hfuc), 2.04 (s, 3 H, CH3). b) Synthesis of [N-carbonyl- (1, l-dicarbomethoxy-ethyl) - (2? 3) - -piperidyl] - (1? 2) - [(aL-fucopyranosyl) - (I?)] - ( 1R, 2R) - -trans-1, 2-cyclohexanediol (3b): A mixture of compound 2b (460 mg, 556 μM), malonic acid dimethyl ester (18 ml), potassium carbonate (1.07 g) and dibenzo-18-crown-6 (264 mg) is stirred for 4 h at 100 ° C. For the treatment, it is diluted with dichloromethane (460 ml) and the organic phase is treated alternately with water and dry ice until the washing water reacts neutrally. The organic phase is dried over sodium sulfate and concentrated under high vacuum at 80 ° C. Chromatography (hexane / ethyl acetate 2: 1) gives compound 3b (367 mg, 84%). H-NMR (300 MHz, CDC13): d = 1.08 (d, 3H, 6-Hfuc), 3.72 (2 s, 6H, 2 COOCH3). b) Synthesis of [N-carbonyl- (1, 1-dicarboxy-ethyl) - (2? 3) - -piperidyl] - (1? 2) - [(aL-fucopyranosyl) - (1?)] - ( 1R, 2R) -trans-l, 2-cyclohexanediol (4b): The deprotection of 4b proceeds as described in 3a. XH-NMR (300 MHz, D20): d = 1.09 (d, 3H, 6-Hfuc), 4.54 (m, 1H, 2-Hcioloh, x), 4.91 (broad s, 1H, 1-Hfuc).

Example 3 a) Synthesis of 2-bromo-N- (2-bromoethyl) -N-carbobenzoxy-ethanamine (le): To an ice-cooled solution based on hydroperoxide of bis- (2-bromoethyl) -amine (4) , 5 g, 14.4 millimoles) in water (25 ml) is added, under vigorous stirring, benzyl ester of chloroformic acid (1.97 ml, 13.8 millimoles) and sodium hydroxide solution 1 M until the pH value is just basic (approximately 24 ml). It is acidified with 1 M hydrochloric acid (2 ml) and extracted with ether (3 x 40 ml). The organic phase is washed with sodium hydrogencarbonate solution and water, dried over magnesium sulfate, concentrated and the residue is chromatographed (hexane / ethyl acetate 5: 1 → 4: 1). The compound is obtained (4.1 g, 81%). XH-NMR (300 MHz, CDC13): d = 3.43, 3.53 [2m, 4H, N (CH2-CH2Br) 2], 3.73 [m, 4H, N (CH2-CH2Br) 2] , 5.17 (s, 2H, CH2Ph), 7.36 (m, 5H, Ph). b) Synthesis of N-carbobenzoxy-4,4-dicarboethoxypiperidine (2c): To a solution based on le (1.1 g, 3 mmol) in dimethylformamide (1 ml) is added malonic acid diethyl ester (303 μl, 2 mmol) and heated to 50 ° C. After the addition of sodium hydride (120 mg, 5 mil mole), it is still stirred for 12 h. The mixture is concentrated under high vacuum and chromatographed with hexane / ethyl acetate 9: 2 → 7: 2. Yield (0.5 g, 69%). XH-NMR (300 MHz, CDC13): d = 1.25 (t, 6H, 2 CH,), 2.08 (m, 4H, C-CH2-CH2N), 3.52 (m, 4H, C-) CH2-CH2N), 4.20 (q, 4H, 2 OCH2CH3), 5.12 (s, 2H, CH2Ph), 7.35 (m, 5H, Ph). c) Synthesis of 4,4-dicarboboxypiperidine (3c): A mixture based on 2c (778 mg, 2.14 mmol) and palladium on carbon (78 mg) in methanol (10 ml) is hydrogenated for 1 h under an atmosphere of hydrogen. For the treatment rí filtra and nr > rnnrnnt rn. ~ > < r (0 ^ mq, pqf.) and use raw in the next stage. "H-NMR (300 MHz, CDC13): d = 1.26 (t, 6H, 2 CH,), 2.06 (m, 4H, C-CH2-CH2N), 2.87 (m, 4H, C -CH2-CH2N), 4.20 (q, 4H, 2 OCH2CH3). d) Synthesis of N-carbonyl-4,4-dicarboethoxy-piperidin- (1? 2) - - [(2,3,4-tri-0-benzyl-a; -L-fucopyranosyl) - (1?)] - (1R, 2R) -trans-l, 2-cyclohexanediol (4c): Compound 4c is synthesized analogously to 2a, starting with and 3c. ? -NRM (300 MHz, CDC13): d = 1.09 (d, 3H, 6-Hfuc), 1.27 (2t, 6H, 2 CH3), 2.02 (m, 4H, C-CH, -CH2N), 4.2 (2q, 4H, 2 OCH2CH3), 7.3 (m, 15 H, 3 Ph). d) Synthesis of N-carbonyl-4,4-dicarboxypiperidyl- (1? 2) - - [(aL-fucopyranosyl) - (1?)] - (1R, 2R) -trans-1, 2-cyclohexanediol (5c): Compound 4d is deprotected analogously to 3a. -NRM (300 MHz, D20) rd = 0.95 (d, 3H, 6-Hfuo), 1.46 (m, 2H), 1.74 (m, 4H), 1.90 (m, 1H), 3.69 (q, 1H, 5-Hfuc), 4.41 (, 1H, 2-Hcyclohex), 4.78 (broad s, 1H, 1-Hfuc).

Example 4 a) Synthesis of [(2, 3, 4-tri-O-acetyl-ar-L-rhamnopyranosyl) - - (1?)] - (1R, 2R) -trans-1, 2-cyclohexanediol (Id): To an open mixture of (IR, 2R) -trans-l, 2-cyclohexanediol (401 mg, 3.5 mmol) and O- (2, 3, 4-tr ^ -O-acetyl-L-rhamnopy-nosyl) -trichloroacetimidate (1.0 g, 2.3 mmol) in dichloromethane (25 ml) is added dropwise a solution in trimethylsilyl trifluoromethylsulphonate 0.1 M (0.23 mmol). After 20 min, it is quenched with sodium hydrogen carbonate (200 mg), filtered, concentrated and the residue is chromatographed with hexane / ethyl acetate 2: 1. Yield: 640 mg, 72%). -NRM (300 MHz, CDC13): d = 1.24 (d, 3H, 6-Hra, 2.00, 2.05, 2.16 (3s, 9H, 3 OAc), 4.92 (d, 1H , 1-Hram), 5.08 (dd, 1H, 4-H ^, 5.21 (dd, 1H, 2-Hra, 5.32 (dd, 1H, 3-Hra. b) Synthesis of N-carbonyl-4-carboethoxy-piperidyl- (1? 2). - [(2,3,4-tri-O-acetyl-aL-rhamnopyranosyl) - (1?)] - - (IR, 2R) -trans-1, 2-cyclohexanediol (2d): Compound 2d is synthesized analogously to 2a. c) Synthesis of N-carbonyl-4-carboxypiperidyl- (1? 2) - [(aL- -ramnopyranosyl) - (l? l) J - (IR, 2R) -trans-l, 2-cyclohexanediol (3d ): To a solution of compound 2d (425 mg, 744 μmol) in methanol (30 ml) is added a solution of 1 M sodium methanolate (1.05 ml). After 1 h, neutralize with Amberlite IR-120, filter and concentrate. To the residue, 1 M sodium hydroxide solution (10 ml) is added. After 1 h, it is again neutralized with Amberlite IR-120, filtered and concentrated. The residue is purified as described in 3a. Yield: 258 mg (83%). d) Synthesis of N-carbonyl-4-carboxypiperidyl- (1? 2) - [(aL- -fucopyranosyl) - (I?)] - (IR, 2R) -trans-l, 2-cyclopentane-diol ( ) The compound is synthesized analogously to 3a.

Example 5 a) Synthesis of N-carbonyl-4-carboxypiperidyl- (1? 2) - [(L- -triityl) - (I?)] - (IR, 2R) -trans-l, 2-cyclohexanediol (lf): Compound lf is prepared analogously to 3a, not reacting (IR, 2R) -trans-l, 2-cyclohexanediol with thioethyl-0-2, 3,4-tri-O-benzyl-aL-fucopyranoside, but with 2, 3, 4-tri-0-benzyl-l-0-toluenesulfonyl-L-threitol (in toluene / 50% sodium hydroxide solution and tetrabutylammonium bromide as a phase transfer catalyst) (see Example 7).

Example 6 c) Synthesis of [N-carbonyl- (1,1-dicarboxy-ethyl) - (2? 2) - (R or S) -pyrrolidyl] - (1? 2) - [(-aL-fucopyranosyl) - (l ?) - - (IR, 2R) -trans-l, 2-cyclohexanediol): The compound 1 g is prepared analogously to 4b, not reacting with 3- (hydroxymethyl) -piperidine, but with prolinol (D or L).

Example 7 a) Synthesis of N-carbonyl-4-carboxypiperidyl- (1? 2) - [(methyl--aD-mannopyranosyl) - (6? 1)] - (1R, 2R) -trans-l, 2-cyclohexa - nodiol (lh): To a mixture based on (IR, 2R) -trans-l, 2-cyclohexanediol (336 mg, 2.884 mmol) in toluene (8 ml), tetrabutylammonium bromide (311 mg, 0.97 mmol) ) and 50% sodium hydroxide solution (4.5 ml) is added a solution based on methyl-2, 3,4-tri-O-benzyl-6-O-toluenesulfonyl-aD-mannopyranoside (1.19 g) 1.93 mmol) in toluene (10 ml). Stir for 12 h at 60 ° C, dilute with ether and wash to neutrality with water. Flash chromatography (toluene / acetone 6: 1-5: 1) provides [(methyl-2,3,4-tri-O-benzyl-aD-mannopynesyl) - (6? 1)] - (IR , 2R) -trans-l, 2-cyclohexanediol which is further processed such as the compound of Example 1.

Example 8 a) Synthesis of N-carbonyl-4-carboxypiperidyl- (1? 2) - [(methyl- -3-D-galactopyranosyl) - (6? l)] - (IR, 2R) -trans-l, 2-cyclohex - xanodiol (li): The compound li is prepared analogously to lh (Example 7), by reacting (IR, 2R) -trans-l, 2-cyclohexanediol with methyl-2, 3,4-tri-0-benzyl-6 -0-toluenesulfonyl-3-D-galactopyroside in toluene / 50% soda lye with tetrabutylammonium bromide as a phase transfer catalyst, and further elaborating the protected precursor as in that of E pg.

Example 9 a) Synthesis of N-carbonyl-4-carboxypiperidyl- (1 → 2) - [galac- topyranosyl- (6 μL)] - (IR, 2R) -trans-1, 2-cyclohexanediol (lk): The compound lk is prepared analogously to lh (Example 8), by reacting (IR, 2R) -trans-l, 2-cyclohexanediol with benzyl-2,3,4-tri-0-benzyl-6-0-trifluoromethanesulfonyl-β-D- -galactopyranoside (in dimethylformamide / 1.2 equivalents of sodium hydride).

Claims (27)

1. - Compound of formula I wherein Z means a pyranose > a pyranosyl radical linked through the C6 position, an alkyl pyranose bound through the C6 position, a furanoside, a furanosyl radical linked through the C5 position, an alkyl furanoside linked through the C5 position. or a polyalcohol that is bonded to A through an arbitrary position, A means oxygen, -CH2- or sulfur, R1 and R2, independently of one another, mean hydrogen, - (CH2) mX1 or CH20 (CH2) mX \ meaning m an integer from 1 to 20, or together they mean a carbocyclic or heterocycle of five or six members with at least one of the substituents R4, R5 or R6, E means nitrogen, carbon or -CH-, R3 means - ( CH2) pC00H, (-C00H) 2, - (CH2) pCH (COOH) 2, - (CH2) pCNH2 (C00H) 2, - (CH2) pC (CH2-C6H5) (COOH) 2, -C0NHC (C00H) 2, meaning p an integer from 0 to 10, or OH OH OOO - I 0 = c. C -NH • NH

OH

OH 0 = 0 = CH- CH ~ or -OH 0 = OH qyr, independently of one another, mean an integer from 0 to 3, n means an integer from 1 to 3. with the proviso that the sum of q , ryn ascend to 4 or 5, R \ R5 and R6, independently of one another, mean H, OH, -OfCHjJ C3 or meaning w an integer from 1 to 18, Y1 and Y2, independently of one another, mean oxygen, -NH- or sulfur and X1, X2, X3 and X4, independently of one another, mean hydrogen,

-NH2, -COOH, -OH, -CH20H, CH2NH2, C ^ C ^ alkyl or C6-C10 aryl. 2. Compound according to claim 1, characterized in that R1 and R2 together form a cyclohexane ring. 3. Compound according to claim 1, characterized in that R1 and R2 together form a cyclopentane ring. 4. Compound according to one of claims 1 to 3, characterized in that A means oxygen.

5. Compound according to one of claims 1 to 4, characterized in that Y1 e'Y2 mean oxygen.

6. Compound according to one of claims 1 to 5, characterized in that n means 1 and qyr mean 2.

7. Compound according to one of claims 1 to 5, characterized in that nyr means 1 and q means 3.

8. - Compound according to a of claims 1 to 5, characterized in that n means 1, q means 0 and r means 3.

9. Compound according to one of claims 1 to 8, characterized in that E means -CH-, R3 means - (CH2) pCOOH and p means 0.

10. Compound according to one of claims 1 to 8, characterized in that E means -CH-. R3 signifies - (CH2) pCH (COOH) 2 and p means 1.

11. Compound according to one of claims 1 to 8, characterized in that E means carbon and R3 signifies - (COOH) 2.

12. Compound according to one of claims 1 to 11, characterized in that Z is a pyranoside.

13. Compound according to claim 12, characterized in that the pyranoside is a -L-fucoside.

14. Compound according to claim 12, characterized in that the pyranoside is a D-mannoside.

15. Compound according to claim 12, characterized in that the pyranoside is an L-rhamnoside.

16. Compound according to claim 12, characterized in that the pyranoside is an L-galactoside.

17. Compound according to claim 12, characterized in that the pyranoside is an L-mannoside.

18. Compound according to one of claims 1 to 11, characterized in that Z is a furanoside.

19. Compound according to claim 18, characterized in that the furanoside is a riboside.

20. Compound according to one of claims 1 to 11, characterized in that Z is a D-mannosyl radical linked through the C6 position.

21. Compound according to one of claims 1 to 11, characterized in that Z is a methyl-D-mannoside radical linked through the C6 position. 22. Compound according to one of claims 1 to 11, characterized in that Z is a radical L-treit-1-yl. 23. Process for the preparation of a compound of the formula I according to one of claims 22, characterized by firstly preparing, under glycosylation at 0 or S, alkylation or CC bond of a functional group of an acceptor of the formula II , having at least two contiguous L1 and L2 functional groups, as well as having the substituents R1 and R2, by an equivalent of a donor of the formula III

III, provided with an activating group L3 and optionally protective groups, intermediate IV after which, under reaction with the reagent of formula V, Y1

V where L4 and L5 have the meaning of labile groups, the activated compound VI is accessed which, by reaction with a cyclic amine carboxylated once or several times or a suitable precursor thereof and optionally after cyclization or carboxylation, as well as after separation of protecting groups, is transformed into the compound of formula I, the variables R1, R2, Y1, Y2, A and Z having the meanings mentioned in claim 1.

24. - Drug containing at least one compound according to one of claims 1 to 22.

25. - Use of a compound according to a of claims 1 to 22, for the preparation of a medicament for the therapy or prophylaxis of a disease that is accompanied by excessive cell adhesion, induced by selectin receptors, in the tissue affected by the disease.

26. Use according to claim 25, characterized in that the disease is a disease of the "circulation" of the heart.

27. Use of a compound according to one of claims 1 to 22, for the preparation of an agent for the diagnosis of a disease accompanied by excessive cell adhesion, induced by selectin receptors, in the tissue affected by the disease.